Last updated:
05/13/2024
Years published: 2011, 2014, 2017, 2020, 2024
NORD gratefully acknowledges Maria Luisa Brandi, MD, PhD, Director of the Donatello Bone Clinic Villa Donatello Hospital, Sesto Fiorentino, Italy; President of the Fondazione F.I.R.M.O. Onlus (Fondazione Italiana per la Ricerca sulle Malattie dell’Osso) Florence, Italy; and Scientific President of the Italian Association for Multiple Endocrine Neoplasia type 1 and 2 (AIMEN 1 e 2 – ONLUS), for assistance in the preparation of this report.
Multiple endocrine neoplasia type 2 (MEN2) is a rare genetic polyglandular cancer syndrome, characterized by the presence of medullary thyroid carcinoma (MTC) and an increased risk of develop other specific tumors affecting other glands of the endocrine system.
The endocrine system is the network of glands that secrete hormones into the bloodstream to reach distant target tissues and organs within the body. Hormones are active molecules, which through their binding to specific receptors in the target cells, regulate the chemical processes (metabolism) that influence vital processes and functions of various organs.
MEN2 endocrine tumors may secrete excessive amounts of hormones into the bloodstream, which can result in a variety of symptoms.
MEN2 syndrome is caused by disease-causing changes (pathogenic variants) in the RET gene and it includes two main clinical subtypes characterized by different clinical characteristics (phenotype) and by different variants in the RET gene:
MEN2A (accounting for 95% of all MEN2 cases), characterized by medullary thyroid cancer (MTC) in association with tumors of the inner part of the adrenal gland called pheocromocytoma (PHEO) or tumors of the parathyroid gland called adenoma, or both in some patients.
MEN2A includes four subvariants:
MEN2B (accounting for less than 5% of all MEN2 cases) is characterized by an earlier onset and more severe MTC that presents in all affected people and by PHEO but not primary hyperparathyroidism (PHPT).
The estimated prevalence of MEN2A is about 1/40,000, while MEN2B varies between 1/350,000 to 1/700,000.
MEN2A can run in families (familial cases) or can occur as the result of a spontaneous genetic change called a new or de novo variant in the RET gene that occurs randomly for no apparent reason in the developing embryo that is not inherited. MEN2B usually occurs as the result of a de novo genetic variant in the developing embryo. Treatment includes surgery and specific medication.
The onset, progression and specific symptoms of each case of MEN2 can vary. Some individuals may only develop mild symptoms; others may develop serious, life-threatening complications. Some individuals may develop symptoms during infancy or early childhood; others may not develop symptoms until adolescence or young adulthood. Some cases of MEN2 may not become apparent until later during adulthood. Clinical features (phenotype) are associated with a specific RET gene variant, and, therefore, MEN2A and MEN2B are associated with different RET gene variants.
Nearly all individuals with MEN2 develop medullary thyroid carcinoma (MTC), usually very early in life. Additional symptoms vary depending upon the specific subtype of the syndrome.
The three endocrine glands most often affected in MEN2 syndrome are the thyroid, the adrenal glands and only in the MEN2A variants, the parathyroids.
Depending on the specific subtypes, signs and symptoms include: (It is important to note that individual cases are highly variable and that not all the affected individuals will develop all the symptoms discussed below).
Multiple Endocrine Neoplasia Type 2A (MEN2A)
The signs and symptom of MEN2A may include:
In addition to the classical MEN2A, there are other two, extremely rare variants which have additional specific symptoms in addition to MTC, PHEO and hyperparathyroidism.
MEN2A associated with cutaneous lichen amyloidosis (CLA), a condition in which a scaly, itchy skin rash develops due to the accumulation of certain proteins (amyloids) in the skin. These skin lesions are particularly evident in the scapular region of the back and have as a classical symptom, an intense itching that improves with sun exposure and worsens during periods of stress. In some patients, the CLA may be present at a young age and manifest prior to the onset of clinically evident MTC, thus serving as a sign for an early diagnosis of the syndrome.
MEN2A associated with Hirschsprung disease, a gastrointestinal condition characterized by absence of certain nerve cell bodies (ganglia) in the smooth muscle wall within a region of the large intestine (i.e., colon). As a result, there is absence or impairment of the involuntary, rhythmic contractions that propel food through the GI tract (peristalsis). Symptoms of Hirschsprung disease include constipation, vomiting, loss of appetite, bloating or swelling (distention) of the abdomen, abnormal accumulation of feces within the colon and widening of the colon above the affected segment (megacolon). Hirschsprung disease can eventually cause diarrhea, dehydration and failure to grow and gain weight at the expected rate (failure to thrive).
Multiple Endocrine Neoplasia Type 2B
The MEN2B subtype accounts for about 5% of all cases of MEN2. MEN2B was formerly called MEN type 3 (MEN3); currently MEN2B is considered a clinically more aggressive variant of MEN2. It is characterized by the occurrence of MTC, PHEO and absence of PHPT, and by additional symptoms. Associated symptoms can vary greatly from one person to another. Some symptoms can be very subtle in some people.
MTC usually occurs earlier in MEN2B than in MEN2A and is usually more aggressive. A neck mass may be detectable during childhood. Most affected children have surgery to remove their thyroid at an early age because MTC can potentially spread (metastasize) at a very early age. A prophylactic thyroidectomy is suggested during the first year of life for children with some specific RET gene variants associated with a particularly aggressive form of MTC.
PHEO occurs in approximately 50% of cases of MEN2B (50% of them being bilateral PHEO), with no differences in occurrence and clinical presentation from individuals with MEN2A.
As commented, people affected with MEN2B may also have additional symptoms that do not occur in the MEN2A subtypes which may include:
Some individuals with MEN2B may develop additional symptoms including a sunken breastbone (pectus excavatum), lax or loose joints, abnormal curvature of the spine, muscle weakness and a “marfanoid habitus”, a condition in which affected individuals tend to be thin with unusually tall stature; long, slender fingers and toes (arachnodactyly) and elongated arms and legs. Note that the term “marfanoid” refers to Marfan syndrome, a distinct genetic disorder in which these findings are characteristic. MEN2B is unrelated to Marfan syndrome other than sharing some similarities in body build.
Familial Medullary Thyroid Carcinoma
By definition, familial medullary thyroid carcinoma (FMTC) must occur in at least four members of a family in the absence of additional signs and symptoms MEN2A or MEN2B such as PHEO or parathyroid adenoma. MTC is less aggressive in this variant than other MEN2A variants and MEN2B familial form than when it is associated with MEN2A or MEN2B. Onset is usually during adulthood. FMTC is now considered a milder variant of MEN2A.
MEN2 is caused by a disease-causing (pathogenic) variant in the RET gene. The RET gene is a proto-oncogene, a gene that, when altered, plays a role in the development of cancer. The RET gene encodes a protein, the RET tyrosine kinase membrane receptor.
When operating normally, the RET protein transduces the signal of RET ligands to the cells, through the activation of its tyrosine kinase activity, exerting several key functions such as control of cell division and regulation of cell death (apoptosis).
The RET protein is a member of the family of receptor tyrosine kinases, which are cell surface glycoprotein receptors that transduce signals for cell growth and differentiation. Activation of RET occurs by the binding of one of its four ligands. Cellular receptors are proteins either inside a cell or on its surface which receive a signal, normally a chemical signal where a protein-ligand binds a protein receptor. The ligand is a chemical messenger released by one cell to signal either itself or a different cell.
All the MEN2-causing variants are activating variants called gain-of-function missense variants, causing a single amino acid substitution in the RET protein. Missense variants are defined as a genetic alteration that produces an amino acid that is different from the usual amino acid at that position.
Activating variants of the RET gene activates the RET receptor and its tyrosine kinase activity, even in absence of ligand, leading to an uncontrolled cell growth, which causes tumor formation in target organs.
About 95% of all cases of MEN2A (including FMTC) are caused by variants in one of the six extracellular cysteine residues of the RET protein (at codons 609, 611, 618, 620, 630 and 634), encoded by exons 10 and 11, with variants at codon 634 being the cause of about 85% of MEN2A cases.
MEN2B is often caused by variants in exons 15 and 16, the p.Met918Thr variant in exon 16 (over 95% of MEN2B cases) and the p. Ala883Phe in exon 15 (about 5% of MEN2B cases). Exons are the regions of genes that code for proteins.
The specific RET gene variants cause the specific signs and symptoms of the disease (genotype-phenotype correlation) and distinguish between MEN2A and MEN2B; the identification of a specific variant in patients can direct the treatment for both MTC and PHEO, and the diagnostic plan for PHPT.
MEN2 is an autosomal dominant genetic disorder. A single copy of a RET gene variant is sufficient for the appearance of the disease. The RET variant may be inherited from one of the parents or occur as a spontaneous genetic change (new variant) that occurs in the developing embryo. The risk of passing the gene variant from an affected parent to a child is 50 percent for each pregnancy, with equal risk for male and female children.
MEN2 affects males and females in equal numbers. It has been estimated to affect 1 in 40,000 people in the general population for all the MEN2A subtypes, and from 1/350,000 to 1/700,000 for the extremely rare MEN2B variant. Some researchers think that many cases of MEN2 go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of these conditions in the general population.
MEN2A is the most common subtype accounting for about 95% of all cases. MEN2B accounts for only 5% of cases.
All cases of MTC (i.e. including both those associated with MEN2 and those arising from sporadic tumors) account for approximately 5-10% of all thyroid cancers.
Affected individuals may receive a clinical diagnosis of MEN2 following a specific clinical evaluation for MEN2-associated tumors, a detailed patient and familial history and the identification of characteristic features.
The characteristic features of MEN2A are the presence of two or more specific endocrine tumors (i.e., MTC, PHEO and parathyroid hyperplasia or adenoma).
Diagnostic features of MEN2B include the identification of MTC, PHEO, multiple neuromas, distinctive facial features and a “marfanoid” habitus. FMTC is diagnosed in individuals with only MTC in at least four family members without the presence of other symptoms associated with MEN2A or MEN2B.
A variety of tests can aid in the diagnosis of MEN2. Such tests include those designed to detect elevated levels of certain hormones in the blood. Identification of elevated hormones in the blood can be an indication of specific endocrine tumors. For example, identification of elevated levels of calcitonin can indicate the presence of MTC, elevated levels of PTH can indicate the presence of a parathyroid tumor and elevated levels of catecholamines may indicate the presence of an active PHEO. A variety of imaging scans may also be done to aid in identifying the size and specific location of tumors and help determine what surgery is needed.
The clinical diagnosis of MEN2 can be confirmed by genetic diagnosis through molecular genetic testing identifying a missense variant of the RET gene.
The treatment of MEN2 may require the coordinated efforts of a team of specialists. Endocrinologists, surgeons, cancer specialists (oncologists) and other healthcare professionals may need to plan the treatment systematically and comprehensively. Treatment is directed toward the specific symptoms that are apparent in each individual and may include surgical removal of tumors and drugs to counteract the effects of excess hormones or replacement of hormones no longer produced by the body (i.e., following surgical removal of a gland).
Specific therapeutic procedures and interventions may vary depending upon numerous factors, such as the specific subtype present, whether C-cell hyperplasia or cancer has developed; the size and type of tumors; the severity of symptoms due to excess hormone production; whether malignant cancer is already present and whether it has spread to lymph nodes or distant sites; an individual’s age and general health and/or other elements.
Decisions concerning the use of interventions should be made by physicians and other members of the healthcare team in careful consultation with the patient, based upon the specifics of their case, a thorough discussion of the potential benefits and risks, patient preference and other appropriate factors.
Because of advancements made in the early MEN2 recognition, in the availability of RET genetic testing for an early MEN2A or MEN2B differential diagnosis, and in the available treatments of MEN2-related tumors, certain serious, life-threatening complications associated with the disorder, such as the spread (metastasis) of MTC or rare complications of a PHEO have been greatly reduced. The result of the genetic test that identifies the specific RET variant can help determine the treatment options for both MTC and PHEO.
The standard therapy for individuals with MEN2 is surgical removal of the thyroid, a procedure called a thyroidectomy. Surgical removal of the thyroid is often performed as a preventive measure, even if cancer or C-cell hyperplasia has not developed yet. Individuals will require life-long hormone replacement therapy of the hormones normally produced by the thyroid. The age of thyroidectomy performance may vary depending upon the specific MEN2 subtype and the specific RET variant. The recommendations on the timing of prophylactic total thyroidectomy and extent of surgery are classified accordingly to the American Thyroid Association (ATA) into three risk levels (highest risk, high risk and moderate risk) based on the specific RET gene variant:
In all three cases, a life-long thyroid hormone supplementation is needed after thyroid removal.
Thyroidectomy can potentially cause the partial or complete ablation of the parathyroid glands causing severe reduction/absence of PTH (hypoparathyroidism). The ability of surgeon is important in identifying parathyroid glands and preserving them to be re-implanted (autotransplant) into the non-dominant forearm, reducing/avoiding the risk of post-operatory hypoparathyroidism. Post-operatory hypoparathyroidism requires life-long treatment with calcium and active vitamin D analogues.
MEN2A PHPT is usually mild, and it can be controlled by medical therapy with medications that mimic the action of calcium on tissues known as calcimimetics or, more frequently, by the surgical removal of the parathyroid gland followed by the re-implantation of some healthy parathyroid tissue into the arm. Because there is a risk of a benign tumor recurring in the healthy parathyroid tissue, transplanting that tissue into the arm would spare affected individuals from being operated on in the same area (i.e., the neck).
The main form of treatment for PHEO is surgery. Surgical removal of one or both adrenal glands is often performed. Both adrenal glands are often removed even in individuals with a PHEO affecting only one gland (unilateral) because of the high risk of the other adrenal gland becoming affected later. The most common surgical procedure for treating PHEO is laparoscopic laparotomy. During this procedure, a small incision is made in the abdomen, a small tube is inserted (laparoscope) through the incision, and the tumor is removed. Before surgery, some affected individuals may need to be treated with alpha-adrenergic blockers and beta-adrenergic blockers to minimize the effects of adrenal hormones. Alpha-adrenergic blockers such as phenoxybenzamine are used to control hypertension. In some patients, beta-adrenergic blockers such as propranolol can also be used to treat hypertension.
In cases where MTC has spread or where malignant transformation of a PHEO has occurred, chemotherapy or radiation therapy may be used.
Before any surgery for individuals with MEN2, screening for the presence of an active PHEO should be performed because of the risk of anesthesia-induced hypertensive crisis.
The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved two orally administered thyrosin kinase inhibitors (TKIs), vandetanib (Caprelsa) in 2011 and cabozantinib (Cabometyx) in 2012, for the treatment of patients with advanced progressive MTC.
Genetic counseling is recommended for affected individuals and their families.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
TEXTBOOKS
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Berkow R., ed. The Merck Manual-Home Edition.2nd ed. Whitehouse Station, NJ: Merck Research Laboratories; 2003:972-974.
Gorlin RJ, Cohen MMJr, Hennekam RCM. Eds. Syndromes of the Head and Neck. 4th ed. Oxford University Press, New York, NY; 2001:462-466.
JOURNAL ARTICLES
Wells SA Jr, Asa SL, Dralle H, et al. American Thyroid Association Guidelines Task Force on Medullary Thyroid Carcinoma. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 2015 Jun;25(6):567-610. doi: 10.1089/thy.2014.0335.
Kloos RT, Eng C, Evans DB et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 2009;19:565–612.
Sippel RS, Kunnimalaiyaan M, Chen H. Current management of medullary thyroid cancer. Oncologist 2008;13:539-547.
White ML, Doherty GM. Multiple endocrine neoplasia. Surg Oncol Clin N Am. 2008;17:439-459.
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INTERNET
Richards ML, Carter SM, Gross SJ, Freeman R. Multiple Endocrine Neoplasia, Type 2. Medscape. Last Update April 1, 2022. Available at: http://www.emedicine.com/MED/topic1520.htm Accessed Feb 8, 2024.
Eng C, Plitt G. Multiple Endocrine Neoplasia Type 2. 1999 Sep 27 [Updated 2023 Aug 10]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1257/ Accessed Feb 8, 2024.
Marini F, Falchetti A, Del Monte F, et al. Multiple Endocrine Neoplasia Type 2. Orphanet. Last update June 2021. Available at: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=653 Accessed Feb 8, 2024.
MEN IIB. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:1162300; Last Update 06/05/2018. Available at: http://omim.org/entry/162300 Accessed Feb 8, 2024.
Miller EJ, Lappin SL. Physiology, Cellular Receptor. [Updated 2022 Sep 14]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554403/Accessed May 13, 2024.
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